Long-term Penetrance of Disease Variants in Genes Prioritized for Genomic Newborn Screening: Evidence from Adult Biobanks

Estimation of long-term penetrance of P/LP variants in 54 genes prioritized for genomic newborn screening in two adult biobanks

A two-cohort study (UK Biobank, n=451,877; Mass General Brigham Biobank, n=53,371) identified pathogenic variants in 54 genes prioritized for genomic newborn screening in 0.15% of adults (~1/650). Medical record review revealed that 70.7% of carriers were undiagnosed, of whom 43.1% had documented symptoms. Corrected penetrance estimates from ICD codes yielded 28.4%, substantially higher than standard estimates. Extrapolated to birth cohorts, results suggest 4,900-5,700 newborns per year in the US carry these variants.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This paper is methodologically important for the genomic newborn screening debate: penetrance is underestimated by diagnostic codes, and many symptomatic adults remain undiagnosed. The argument for these 54 genes in a newborn screening panel is thereby strengthened. A preprint on a major public health policy topic.